Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry.

AIMS: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. METHODS AND RESULTS: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. CONCLUSION: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator.

Return-to-Play for Elite Athletes With Genetic Heart Diseases Predisposing to Sudden Cardiac Death.

BACKGROUND: People diagnosed with genetic heart diseases (GHDs) associated with sudden cardiac death (SCD) have historically been restricted from competitive sports. Recent data documenting return-to-play (RTP) experiences following shared decision making (SDM) suggest that cardiac event rates for athletes with a GHD are lower than previously described, thereby suggesting an opportunity to reconsider this paradigm. OBJECTIVES: The purpose of this study was to evaluate clinical outcomes among National Collegiate Athletic Association Division I university and professional athletes diagnosed with a GHD. METHODS: A multicenter retrospective analysis was performed to examine demographics, clinical characteristics, RTP outcomes, and cardiac events among elite athletes with a GHD. RESULTS: A total of 76 elite (66%, Division I, 34% professional) athletes (age 19.9 ± 5 years, 28% women) diagnosed with a GHD (hypertrophic cardiomyopathy [53%], long QT syndrome, long QT syndrome [26%]) comprise this cohort. Most athletes were asymptomatic (48 of 76, 63%) before diagnosis and had their GHD detected during routine preparticipation cardiovascular screening. Most athletes (55 of 76, 72%) were initially disqualified from their sport but subsequently opted for unrestricted RTP after comprehensive clinical evaluation and SDM. To date, (mean follow-up 7 ± 6 years), only 1 exercise-related (1.3%) and 2 nonexercise-related GHD-associated adverse cardiac events occurred. There have been no fatalities during follow-up. CONCLUSIONS: This is the first study describing the experience of athletes with a known SCD-predisposing GHD who are competing at the elite level. After careful evaluation, risk stratification, and tailoring of their GHD therapy, RTP following SDM appears associated with low, nonfatal events rates at elite levels of sport.

Association Between Syncope Trigger Type and Risk of Subsequent Life-Threatening Events in Patients With Long QT Syndrome.

Importance: Syncope is the most powerful predictor for subsequent life-threatening events (LTEs) in patients with congenital long QT syndrome (LQTS). Whether distinct syncope triggers are associated with differential subsequent risk of LTEs is unknown. Objective: To evaluate the association between adrenergic (AD)- and nonadrenergic (non-AD)-triggered syncopal events and the risk of subsequent LTEs in patients with LQT types 1 to 3 (LQT1-3). Design, Setting, and Participants: This retrospective cohort study included data from 5 international LQTS registries (Rochester, New York; the Mayo Clinic, Rochester, Minnesota; Israel, the Netherlands, and Japan). The study population comprised 2938 patients with genetically confirmed LQT1, LQT2, or LQT3 stemming from a single LQTS-causative variant. Patients were enrolled from July 1979 to July 2021. Exposures: Syncope by AD and non-AD triggers. Main Outcomes and Measures: The primary end point was the first occurrence of an LTE. Multivariate Cox regression was used to determine the association of AD- or non-AD-triggered syncope on the risk of subsequent LTE by genotype. Separate analysis was performed in patients with ß-blockers. Results: A total of 2938 patients were included (mean [SD] age at enrollment, 29 [7] years; 1645 [56%] female). In 1331 patients with LQT1, a first syncope occurred in 365 (27%) and was induced mostly with AD triggers (243 [67%]). Syncope preceded 43 subsequent LTEs (68%). Syncopal episodes associated with AD triggers were associated with the highest risk of subsequent LTE (hazard ratio [HR], 7.61; 95% CI, 4.18-14.20; P < .001), whereas the risk associated with syncopal events due to non-AD triggers was statistically nonsignificant (HR, 1.50; 95% CI, 0.21-4.77; P = .97). In 1106 patients with LQT2, a first syncope occurred in 283 (26%) and was associated with AD and non-AD triggers in 106 (37%) and 177 (63%), respectively. Syncope preceded 55 LTEs (56%). Both AD- and non-AD-triggered syncope were associated with a greater than 3-fold increased risk of subsequent LTE (HR, 3.07; 95% CI, 1.66-5.67; P ≤ .001 and HR, 3.45, 95% CI, 1.96-6.06; P ≤ .001, respectively). In contrast, in 501 patients with LQT3, LTE was preceded by a syncopal episode in 7 (12%). In patients with LQT1 and LQT2, treatment with ß-blockers following a syncopal event was associated with a significant reduction in the risk of subsequent LTEs. The rate of breakthrough events during treatment with ß-blockers was significantly higher among those treated with selective agents vs nonselective agents. Conclusion and Relevance: In this study, trigger-specific syncope in LQTS patients was associated with differential risk of subsequent LTE and response to ß-blocker therapy.

Bilateral cardiac sympathetic denervation in patients with congenital long QT syndrome.

BACKGROUND: Long QT syndrome (LQTS) is a potentially lethal yet treatable genetic heart disease for which left cardiac sympathetic denervation (LCSD) is a class I recommendation. Recent reports have suggested bilateral cardiac sympathetic denervation (BiCSD) as the initial surgical denervation therapy in LQTS. OBJECTIVE: The purpose of this study was to determine the frequency and settings in which BiCSD was used in a tertiary referral center with expertise in LCSD. METHODS: We performed a retrospective review of 234 out of 1638 patients with LQTS who underwent sympathetic denervation (14%) at our institution to identify the subset of patients who underwent BiCSD. Cardiac events (CEs) before LCSD, after LCSD, and after the completion of BiCSD were recorded and defined as being an appropriate implantable cardioverter-defibrillator shock, arrhythmic syncope, or sudden cardiac arrest. RESULTS: Only 11 patients (4.7%; 6 females [55%]) had BiCSD at our institution. Patients who received BiCSD trended toward being younger at diagnosis (6 ± 15 years vs 14 ± 13 years; P = .06) and being more likely to be symptomatic (73% vs 53%; P = .07) than the larger LCSD-only cohort. Continued CEs post-LCSD (3.8 CEs per patient on average) was the predominant determinant to return for BiCSD. Over 60 combined years of follow-up, 4 patients have not had a CE post-BiCSD while the other 7 patients average 3.6 nonlethal CEs. CONCLUSION: Less than 5% of all patients receiving denervation therapy underwent BiCSD. When BiCSD was chosen, it was almost always done in a staged sequential manner beginning with LCSD first and when driven by the arrhythmogenicity of the LQTS substrate, despite otherwise optimized guideline-directed therapies.

Repeatability of ventricular arrhythmia characteristics on the exercise-stress test in RYR2-mediated catecholaminergic polymorphic ventricular tachycardia.

AIMS: In catecholaminergic polymorphic ventricular tachycardia (CPVT), the exercise-stress test (EST) is the cornerstone for the diagnosis, risk stratification, and assessment of therapeutic efficacy, but its repeatability is unknown. We aimed to test the repeatability of ventricular arrhythmia characteristics on the EST in patients with CPVT. METHODS AND RESULTS: EST-pairs (ESTs performed within 18 months between 2005 and 2021, on the same protocol, and without or on the exact same treatment) of patients with RYR2-mediated CPVT from two specialized centres were included. The primary endpoint was the repeatability of the maximum ventricular arrhythmia score [VAS: 0 for the absence of premature ventricular contractions (PVCs); 1 for isolated PVCs; 2 for bigeminal PVCs; 3 for couplets; and 4 for non-sustained ventricular tachycardia]. Secondary outcomes were the repeatability of the heart rate at the first PVC and the ΔVAS (the absolute difference in VAS between the EST-pairs). A total of 104 patients with 349 EST-pairs were included. The median duration between ESTs was 343 (interquartile range, 189-378) days. Sixty (17.2%) EST-pairs were off therapy. The repeatability of the VAS was moderate {Krippendorf α, 0.56 [95% confidence interval (CI), 0.48-0.64]}, and the repeatability of the heart rate at the first PVC was substantial [intra-class correlation coefficient, 0.78 (95% CI, 0.71-0.84)]. The use of medication was associated with a higher odds for a ΔVAS > 1 (odds ratio = 3.52; 95% CI, 2.46-4.57; P = 0.020). CONCLUSION: The repeatability of ventricular arrhythmia characteristics was moderate to substantial. This underlines the need for multiple ESTs in CPVT patients and CPVT suspicious patients and it provides the framework for assessing the therapeutic efficacy of novel CPVT therapies.

Outcomes of Athletes With Genetic Heart Diseases and Implantable Cardioverter-Defibrillators Who Chose to Return to Play.

OBJECTIVE: To evaluate outcomes for athletes with a genetic heart disease (GHD) and an implantable cardioverter-defibrillator (ICD) after return-to-play (RTP) approval. PATIENTS AND METHODS: We conducted a retrospective review of athletes with GHD and an ICD who were evaluated and treated in Mayo Clinic's Genetic Heart Rhythm Clinic between July 2000 and July 2020. Data on frequency of GHD-associated breakthrough cardiac events (BCEs), inappropriate shocks, and ICD-related complications were collected and analyzed. RESULTS: There were 125 (57 [45.6%] female) GHD-positive athletes with an ICD (mean age at RTP was 19.8±11.6 years); 56 of 125 (44.8%) had long QT syndrome. Overall, 42 ventricular fibrillation-terminating ICD therapies were given to 23 athletes (18.4%) over an average follow-up of 3.6±3.5 years. Athletes with an ICD were more likely to experience a BCE during athletic follow-up (n=28 of 125, 22.4%) compared with those without an ICD (n=4 of 533, 0.8%; P<.0001). The BCE rate for athletes with ICDs was 6.3 events per 100 athlete-years of follow-up; this included 5.1 ventricular fibrillation-terminating events per 100 athlete-years compared with 0.3 BCEs per 100 patient-years for athletes without ICDs. In total, 6 (4.8%) athletes experienced at least one inappropriate shock (1.34 per 100 athlete-years) and 28 (29.6%) athletes had at least one other device-related complication (5.02 per 100 patient-years). However, none of these other complications occurred during sports. CONCLUSION: This 20-year single-center study provides the longest spanning retrospective review of outcomes for athletes with ICDs given RTP approval. For athletes with GHD and an ICD, no sports-associated deaths or reports of sports-related ICD damage occurred.

Diagnostic accuracy of the 12-lead electrocardiogram in the first 48 hours of life for newborns of a parent with congenital long QT syndrome.

BACKGROUND: Long QT syndrome (LQTS) is an autosomal dominant disorder characterized by a prolonged QT interval. Electrocardiographic (ECG) screening in the first 48 hours of life may be misleading, even in newborns with a genotype-positive LQTS parent. OBJECTIVE: The purpose of this study was to determine the ECG's diagnostic accuracy in the first 48 hours of life for neonates born to a parent with LQTS. METHODS: We conducted a retrospective review of all neonates born at Mayo Clinic to a parent with ≥1 pathogenic variant in a LQTS-causative gene who had least 1 ECG in the first 48 hours and genetic test results were available. The sensitivity and specificity of the diagnostic ECG were calculated using Bazett's heart rate-corrected QT (QTc) thresholds of 440, 450, 460, and 470 ms. RESULTS: Overall, 74 newborns (36 females [49%]) were included (mean QTc interval on the first ECG 489 ± 54 ms; 50 [68%] LQTS genotype-positive). The mean QTc interval in the first 48 hours for neonates that ultimately were genotype-positive was greater (506 ± 52 ms) than that for genotype-negative neonates (455 ± 41 ms) (P = .0004). When using a recommended threshold QTc interval of ≥440 ms, 6 of 50 genotype-positive neonates (12%) were missed (underdiagnosed) and 17 of 24 genotype-negative neonates (71%) were overdiagnosed (sensitivity 88%; specificity 29%). CONCLUSION: The newborn ECG should not be used in isolation to make the diagnosis of LQTS since it will result in many misclassifications. Genetic testing must be initiated before discharge, and proper anticipatory guidance is vital while awaiting test results.

Genome sequencing in a genetically elusive multigenerational long QT syndrome pedigree identifies a novel LQT2-causative deeply intronic KCNH2 variant.

BACKGROUND: Most of the long QT syndrome (LQTS) stems from pathogenic variants in KCNQ1, KCNH2, or SCN5A. However, ∼10%-20% of LQTS index cases remain genotype-negative. OBJECTIVE: The purpose of this study was to identify and characterize functionally a novel LQTS genetic substrate in a multigenerational, "genotype-negative" LQTS pedigree. METHODS: The patient was a 40-year-old woman with a history of syncope, seizures, ventricular fibrillation, and a family history of LQTS and sudden death. Commercial genetic testing of all LQTS-causative genes was negative. Genome sequencing was performed on 6 affected family members. Patient-specific and CRISPR/Cas9 "gene-corrected" isogenic control induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated. RESULTS: No ultrarare, nonsynonymous heterozygous variants cosegregated among the 6 LQTS phenotype-positive individuals. Instead, a deep intronic KCNH2 variant (c.3331-316G>T) was present in all affected individuals. Reverse transcription polymerase chain reaction analysis of patient-specific iPSC-CM-derived RNA revealed that c.3331-316G>T creates a novel 89 base-pair exon that results in a frameshift variant (p.S1112Pfs∗171). Action potential duration (APD90) was significantly longer in p.S1112Pfs∗171-iPSC-CMs (602.4 ± 12.2 ms; n =70) compared to isogenic control iPSC-CMs (425.7 ± 9.3 ms; n = 61; P <.0001). Further, field potential duration was significantly longer in p.S1112Pfs∗171-iPSC-CMs (358.9 ± 7.7 ms; n = 65) compared to isogenic control iPSC-CMs (282.2 ± 10.8 ms; n = 51; P <.0001). CONCLUSION: A novel deep intronic KCNH2 variant was identified in a multigenerational, genetically elusive LQTS pedigree. The iPSC-CMs establish that the variant is the monogenetic cause for this family's LQTS. Deep intronic variants within the 2 most common LQTS-susceptibility genes should be considered in patients with seemingly genetically elusive LQTS.

Return-to-Play for Athletes With Long QT Syndrome or Genetic Heart Diseases Predisposing to Sudden Death.

BACKGROUND: Within the last 5 years, cardiac society guidelines have begun to acknowledge shared decision making (SDM) for the athlete with sudden cardiac death-predisposing genetic heart diseases (GHDs), such as long QT syndrome (LQTS), and the possibility for that athlete's return to play. Previously, international guidelines embraced a de facto disqualification for all such athletes including athletes with solely a positive genetic test in Europe. OBJECTIVES: This study sought to examine the prevalence and outcomes of athletes with sudden cardiac death-predisposing GHDs, particularly LQTS, after their return to play. METHODS: A retrospective review of the electronic medical record was performed on all athletes with GHD, with a primary analysis for those with LQTS, who were evaluated, risk stratified, and treated in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic by a single genetic cardiologist between July 1, 2000, and July 31, 2020. RESULTS: There were 672 athletes with GHD overall including 494 athletes with LQTS (231 female athletes [46.8%]; mean age at diagnosis 14.8 ± 10.5 years; mean follow-up 4.2 ± 4.8 years) who were given return-to-play approval. Overall, 79 of 494 athletes with LQTS (16.0%) were symptomatic before diagnosis, and 58 (11.7%) had an implantable cardioverter-defibrillator. In 2,056 combined years of follow-up, there was no GHD-sports associated mortality. Instead, 29 patients (5.9%) had ≥1 nonlethal, LQTS-associated breakthrough cardiac event. Of those, 15 (3.0%) were athletes at the time of the breakthrough cardiac event, with 3 (0.6%) experiencing a sports-related breakthrough cardiac event, and 12 (2.4%) a non-sports-related event. Overall, the event rate was 1.16 nonlethal events per 100 athlete-years of follow-up. CONCLUSIONS: This 20-year single center experience challenges the status quo of disqualification for all athletes with LQTS and provides additional observational evidence, albeit from a single center, in support of the more contemporary SDM approaches to this complex issue.